Isoquinoline-steroid conjugates and uses thereof

Abstract

Provided herein are compounds and pharmaceutical compositions useful in modulating kinase activity, and related diseases. Also provided herein are methods of treating an eye disease or disorder in a subject. Also provided herein are methods of reducing intraocular pressure in a subject. Also provided herein are methods of modulating kinase activity in a cell. Also provided herein are methods of making the compounds provided herein, and compounds useful for the preparation of the compounds provided herein.

What is claimed is: 
     
       1. A method of treating an eye disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The method of  claim 1 , wherein the eye disease or disorder comprises glaucoma, a neurodegenerative eye disease or disorder, dry eye, ocular hypertension, an ocular inflammatory disease or disorder, or a combination thereof. 
     
     
       3. The method of  claim 2 , wherein the ocular inflammatory disease or disorder comprises uveitis, a corneal ulcer, endophthalmitis, an autoimmune disease of the cornea or ocular surface, an ophthalmic manifestation of HIV disease, or a combination thereof. 
     
     
       4. The method of  claim 1 , wherein the administration is topical administration to the eye. 
     
     
       5. A method of treating an eye disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the formula:
   R 8 —R 10 —R 11  
 
 or a pharmaceutically acceptable salt thereof; 
 wherein 
 R 8  is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 10  is 
       
       
         
           
           
               
               
           
         
          and 
         R 11  is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       6. The method of  claim 5 , wherein
 R 10  is 
 
       
         
           
           
               
               
           
         
          and 
         R 11  is 
       
       
         
           
           
               
               
           
         
       
     
     
       7. The method of  claim 5 , wherein
 R 10  is 
 
       
         
           
           
               
               
           
         
          and 
         R 11  is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       8. The method of  claim 5 , wherein
 R 11  is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       9. The method of  claim 5 , wherein
 R 10  is 
 
       
         
           
           
               
               
           
         
          and 
         R 11  is 
       
       
         
           
           
               
               
           
         
       
     
     
       10. The method of  claim 5 , wherein
 R 10  is 
 
       
         
           
           
               
               
           
         
          and 
         R 11  is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       11. The method of  claim 5 , wherein
 R 11  is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       12. The method of  claim 5 , wherein
 R 10  is 
 
       
         
           
           
               
               
           
         
          and 
         R 11  is 
       
       
         
           
           
               
               
           
         
       
     
     
       13. The method of  claim 5 , wherein
 R 10  is 
 
       
         
           
           
               
               
           
         
          and 
         R 11  is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       14. The method of  claim 5 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       15. The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       16. The method of  claim 5 , wherein the eye disease or disorder comprises glaucoma, a neurodegenerative eye disease or disorder, dry eye, ocular hypertension, an ocular inflammatory disease or disorder, or a combination thereof. 
     
     
       17. The method of  claim 16 , wherein the ocular inflammatory disease or disorder comprises uveitis, a corneal ulcer, endophthalmitis, an autoimmune disease of the cornea or ocular surface, an ophthalmic manifestation of HIV disease, or a combination thereof. 
     
     
       18. The method of  claim 5 , wherein the administration is topical administration to the eye.